Structural Connectivity Between Rostral Anterior Cingulate Cortex and Amygdala Predicts First Onset of Depressive Disorders in Adolescence

Background: Adolescent-onset depressive disorders (DDs) are associated with deficits in the regulation of negative affect across modalities (self-report, behavioral paradigms, and neuroimaging), which may manifest prior to first-onset DDs. Whether the neurocircuitry governing emotional regulation predates DDs is unclear. This study tested whether a critical pathway for emotion regulation (rostral anterior cingulate cortex–amygdala structural connectivity) predicts first-onset DDs in adolescent females. Methods: Diffusion tensor imaging data were acquired on adolescent females (n = 212) without a history of DDs and the cohort was reassessed for first-onset DDs over the next 27 months. Results: A total of 26 girls developed first onsets of DDs in the 27 months after imaging. Multivariate logistic regression showed that lower weighted average fractional anisotropy of uncinate fasciculus tracts between the rostral anterior cingulate cortex and amygdala prospectively predicted first onset of DDs (adjusted odds ratio = 0.44, p = .005), above and beyond established risk factors including baseline depression symptom severity, history of anxiety disorders, parental history of depression, parental education, and age. Conclusions: This study provides evidence for the first time showing that aberrant structural connectivity between the rostral anterior cingulate cortex and amygdala prospectively predates first onset of DDs in adolescent females. These results highlight the importance of a well-established neural circuit implicated in the regulation of negative affect as a likely etiological factor and a promising target for intervention and prevention of DDs.